5-(2-Aminoethyl)-2,3-dioxopiperazines

ABSTRACT

1-Hydrocarbon-5-(2-aminoethyl)-4-aryl-2,3-dioxopiperazines active as antiviral agents are disclosed.

United States Patent Lumsford et al.

[ June 24, 1975 5-( Z-AMINOETHYL)-2,3-DIOXOPIPERA- ZINES Inventors: CarlDalton Lunsford, Richmond;

Albert Duncan Cale, Jr., Mechanicsville, both of Va.

A. H. Robins Company, Incorporated, Richmond, Va.

Filed: Feb. 29, 1972 Appl. No: 230,460

Related US. Application Data Continuation-in-part of Ser. No. 32,346,April 24, 1970, abandoned.

Assignee:

[52] US. CL... 260/268 DK; 260/2472 A; 424/250 [51] Int. Cl "007d 51/72[58] Field of Search 260/268 DK Primary ExaminerDonald G. Daus AssistantExaminer.l0se Tovar 5 flClaims, No Drawings 15-(Z-AMINUETHYL)-2,3-DTOXOPIPERAZ1INES The present application is acontinuationin-part of copending application Ser. No. 32,346, filed Apr.27, 1970 now abandoned.

The present invention relates to heterocyclic organic compounds whichmay be referred to broadly as substi tuted piperazines and is moreparticularly concerned with l-hydrocarbon-5-(2-aminoethyl)-4phenyl-2,3-dioxopiperazines, compositions thereof andmethods of CO- making and using the same.

The invention is especially concerned with novel compounds having theformula:

R 4 l O N K 1" CH2 CHaAm Formula I wherein;

R is selected from the group consisting of loweralkyl, lower-cycloalkyland phenyllower-alkyl;

R is selected from the group consisting of phenyl,

halophenyl,

fections of the myxovirus group including, but not limiting thereto,Parainfluenza, Types 1 and 111, Long Strain of Respiratory SyncytialVirus and Type A lnfluenza infections. The antiviral activity of thenovel compounds has been demonstrated by standard in vitro and in vivotechniques including tissue culture and mouse protection tests.

The antiviral activity of some of the novel compounds of the presentinvention is shown below in Table l.

' TABLE I Compound Influenza Type lll RS Example 1 Active Example 2Active Example 7 Active Example 8 Active Active Active 'Parainflucnza,Type 111. Long Strain of Respiratory Syncytial Virus.

It is, accordingly, an object of the present invention to provide newand useful l-hydrocarbon-5-(2-aminoethyl)-4-phenyl-2,3-dioxo-piperazines. A further object is toprovide l-hydrocarbon- S-(Z-aminoethyl)-4-phenyl-2,3-dioxopiperazinesuseful as antiviral agents. A still further object is to provide methodsfor preparing the new and useful compounds described herein. Otherobjects of the invention will be apparent to one skilled in the art, andstill other objects will become apparent hereinafter.

The term loweralkyl as used herein includes straight and branched chainradicals of up to eight carbon atoms inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl,tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.Lower-alkoxy" has a formula -O-loweralkyl.

The term phenyl as used in the specification and claims hereof refers tothe unsubstituted phenyl radical or to a phenyl radical substituted byany radical or radicals which are not reactive or otherwise interferingunder the conditions of reactions such as lower-alkoxy, lower-alkyl,trifluormethyl, halo, and the like. The substituted phenyl radicals havepreferably no more than one to three substituents such as those givenabove and, furthermore, these substituents can be in various availablepositions of the phenyl nucleus and, when more than one substituent ispresent, can be the same or different and can be in various positioncombinations relative to each other. Lower-alkyl and lower-alkoxysubstituents each have preferably one to four carbon atoms which can bearranged as straight or branched chains.

The term cycloalkyl as used herein includes primarily cyclic alkylradicals containing three to nine carbon atoms inclusive and encompassessuch groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,methylcyclohexyl, and cyclooctyl.

When halogen is referred to herein, preferably but not necessarily, ahalogen of atomic weight in excess of 18 but not greater than 80, isemployed. Among the suitable amino radicals included within the symbol-Am are primary, secondary and tertiary amino radicals, such asunsubstituted amino (-Nl-l lower-alkylamino, di-lower-alkylamino, basicsaturated monocyclic heterocyclic radicals having up to a maximum of 12carbon atoms as exemplified by piperidino, pyrrolidino, morpholino,piperazino, loweralkylpiperazino (e.g., C- or N -methylpiperazino), and4-hydroxy-4-phenylpiperidino.

The pharmaceutically acceptable non-toxic salts include the organic andinorganic acid addition salts, for example, those prepared from acidssuch as hydrochloric, sulfuric, sulfamic, tartaric, fumaric,hydrobromic, hydroiodic, glycolic, citric, maleic, phosphoric, succinic,and the like. Such salts are prepared by conventional methods.

The preparation of the l-hydrocarbon-5-(2-aminoethyl)-4-phenyl-2,3-dioxopiperazines (I) may be accomplished bymixing and reacting the appropriately 3 substituted-(2-haloethyl)-2,3-dioxopiperazine (II) with an amine (Ill). Thereaction sequence is illustrated by the following:

' EXAMPLE 1 2,3-Dioxol -isopropyl-5-( 2-morpholinoethyl )-4-phenylpiperazine.

N TcH cn Am 0 N A suitable procedure for carrying out the process of To100 ml. of morpholine was added 10 g. (0.04

the invention is as follows:

.The conversion of the halo-compound (II) to a 1- hydrocarbon-S-(2-aminoethyl)-4-aryl-2,3-dioxopipermole) of5-(2-chlorophenyl)-2,3-dioxo-l-isopropyl-4- phenylpiperazine and thesolution was refluxed for 4 hours. The solution was concentrated invacuo and the residue partitioned between chloroform and dilute sodiumhydroxide solution. The chloroform layer was dried with sodium sulfateand concentrated in vacuo. The residue was crystallized twice fromisopropyl ether-methanohthe product weighed 8.5 g. (61%) and melted atl9O-l9 5C.

Analysis:

Calculated for C H N O Found:

reaction is substantially complete. The reaction time required may varydepending upon the particular amine used, but 2 hours is generallysufficient for complete reaction. A solvent, e.g., ethanol, isopropanol,dioxane, ethylene glycol, or the like, may be used, in which case longerreaction times of up to 8 hours are necessary. The excess amine andsolvent are removed by stripping using a suitable heat source. Theresidue is isolated and purified in any appropriate conventional manner.

The reaction of the halo-compound (II) with an excess of a volatileamine, such as dimethylamine, may be conducted in a stainless steelpressure vessel employing a suitable reaction solvent, e.g., ethanol,isopropanol, dioxane, or the like. The reactants together with thesolvent are sealed in the pressure vessel and heated to a suitabletemperature as, for example, about 75200C. The reaction may occur atroom temperature, but elevated temperatures are usually advantageouslyemployed to shorten the reaction period. The length of the reaction timevaries with the type of amine-and the temperature range employed, 2hours of heating vat temperatures within the range of lO0-l50C. usuallybeing sufficient to complete the reaction. A longer heating period mayfrequently be used without any resultant harm to the product. Thepressure vessel is cooled and any excess amine and solvent are removed,as under reduced pressure using a suitable heat sourceas, for example,steam. The residue may then be isolated and purified as above.

-The examples immediately following illustrate the preparation ofl-hydrocarbon-5-(2-aminoethyl)-4'- aryl-Z,3-dioxopiperazines accordingto the invention.

Using the process described in Example I, the following compounds areprepared from the stated starting materials:

. 2,3-dioxo-1-isopropyl-4-phenyl-5-(2- pyrrolidinoethyl) piperazine isprepared by reacting5-(2-chl0r0ethyl)-2,3-dioxol-isopropyl-4-phenylpiperazine andpyrrolidine;

'2,3-dioxol -isopropyl-4-(o-chlorophenyl )5-( 2- piperidinoethyl)piperazine is prepared by reacting 5-(2-chloroethyl)-2,3-dioxo-1-isopropyl-4-(o-chlorophenyl)piperazine and piperidine; Y

2,3-dioxo-l-ethyl-5-[2-(4-hydroxy-4-phenylpiperidino)ethyl]-4-phenylpiperazine is prepared by reacting5-(2-chloroethyl)12,3-dioxo-' 1-ethyl-4-phenylpiperazine and4-hydroxy-4- phenylpiperidine;

EXAMPLE 2 2,3rDioxo-5-(2-dimethylaminoethyl l -isopropyl-4-phenylpiperazine. p To a solution of 4 g. (0.088 mole) of dimethylaminein 250 ml. of absolute ethanol was added 13 g. (0.044

mole) of 5-( 2-chloroethyl )-2,3-dioxol -isopropyl-4- phenylpiperazine.The mixture was heated in a steel bomb at 140C. for 18 hours. Thesolution was concentrated in vacuo and the residue partitioned betweenchloroform and dilute sodium hydroxide solution. The chloroform layerwas concentrated and the residue dissolved in 75 percent methyl isobutylketone percent methanol and the solution was treated with etherealhydrogen chloride. The hydrochloride salt melted above 270C. Thehydrochloride salt was partitioned between chloroform and dilute sodiumhydroxide solu tion, the chloroform layer was separated and concentratedin vacuo; the residue was crystallized from ethyl acetatemethanol. Thefree base weighed 6 g. and melted at 173175C.

EXAMPLE 4 2,3-Dioxo-1-ethyl-5-(2-morpholinoethyl)-4phenylpiperazine.

A solution of 20.0 g. (0.0715 mole) of 5-(2-chloroethyl)-2,3dioxo-1-ethyl-4-phenylpiperazine and 150 ml. ofmorpholine was refluxed 4 hours. The reaction was concentrated atreduced pressure and the residual material was partitioned betweenchloroform and dilute sodium hydroxide solution. The chloroform solutionwas dried over sodium sulfate and concentrated. The residue wascrystallized from ethyl acetate. The product weighed 16 g. (67%) andmelted at 124-126C.

Calculated for C -,H N O Found:

Analysis:

C, 67.30; H, 8.31; N, 13.89 C, 67.34; H, 8.22; N, 13.89

Analysis:

Calculated for C H N O Found:

C, 65.23; H, 7.61; N, 12.68 C, 65.12; H. 7.52; N, 12.50

Using the process described in Example 2, the following compounds areprepared from the stated starting materials:

2,3-dioxo-1-isopropyl-5-(2-methylaminoethyl)-4-(omethoxyphenyl)piperazineis prepared by reacting 5-(2-chloroethyl)-2,3-dioxo-1-isopropyl-4-(omethoxyphenyl)piperazine and methylamine;

2,3-dioxo-1-isopropyl-5-(2-isopropylaminoethyl)-4- phenylpiperazine isprepared by reacting5-(2-chloroethy1)-2,3-dioxol-isopropyl-4-phenylpiperazine andisopropylamine;

and

2,3-dioxo-5 -(2-dimethylaminoethyl)-1-isopropyl-4-(o-methylphenyl)piperazine is prepared by reacting 5-(2-chloroethyl)-EXAMPLE 5 5-( Z-Dimethylaminoethyl )-2,3-dioxol -methyl-4phenylpiperazine.

Analysis:

Calculated for C H N o z C, 65.42; H, 7.68; N, 15.26

Found: C, 65.10; H, 7.85; N, 15.08

2,3-dioxo1-isopropyl-4-(o-methylphenyl)piperazine EXAMPLE 6 dd' th 1yamme 5-(2-D1methylammoethyl)-2,3-d1oxo-1-ethyl4-phenyl- EXAMPLE 3piperazine.

2,3-Dioxo-1-methyl-5-(2-morpholinoethyl)-4-phenyl- A solution of 27grams (0.096 mole) of 5-(2 piperazine.chloroethyl)-2,3-dioxo-1-ethyl-4-phenylpiperazine and Analysis:Calculated for c r-1 N 0 Found:

8.6 g. (0.192 mole) of dimethylamine in 500 ml. of ethanol was heated ina steel bomb on the steam bath for 18 hours. The reaction mixture wasconcentrated in vacuo and the residue partitioned between dilute sodiumhydroxide solution and chloroform while being kept ice cold. Thechloroform layer was concentrated and the residue crystallized threetimes from ethyl acetate; m.p. 104l23C. The solid was partitionedbetween ethyl acetate and dilute hydrochloric acid. The aqueous acidsolution was made basic with sodium hydroxide solution, thebase-insoluble oil extracted with chloroform, the chloroform extractsconcentrated and the residue crystallized from ethyl acetate-isopropylether mixture. The product weighed 2.0 g. and melted at 123-125C.

2,3-dioxo-l-cyclohexyl-4-phenylpiperazine and 100 Analysis: Calculatedfor c,,H N,o,: C, 66.41; H, 8.01; N, 14.52

Found: C, 66.14; H, 7.98; N, l4.6 6

EXAMPLE 7 l 5 y Typical blend for encapsulation. Mg. per capsulel-Cyclohexyl-2,3-dioxo-5-(2-morpholinoethyl)-4- A i i n salt 250-phenylpiperazine. v 1 r v 28:8 A mixture of 20 g'.' (0.06 mole) of-(2-chloroethyl)- [l0 ot I 1. 00-0 Unifortnly blend the selected activeingredient with ml. of morpholine was refluxed 4 hours. The reactionlactose and starch and encapsulate the. blend.

mixture was concentrated under reduced'pressure and the residualmaterial was partitioned between chloroform and d lute sodium hydroxideSOlUUOH. The chlorol5 (2) lnjecmble I I Y H per cm form solution wasdried over sodium sulfate and concentrated. The solid residue wascrystallized from ethyl Active ingredient. as saltacetate-dimethylformamide to give 16 g. (69%) of grs a l'z'iitilrvfgel.%..nclhlorobutanol v w./ v. 0.5 product which melted at l87l88C.

Analysis Calculated for C H N O z C, 68.54; H, 8.l 0 N, 90

. ,Found: C, 68.67, H, 8.2 4; N, ll 03 -chloroethyl)- EXAMPLE 8 Preparesolution, clarify by filtration, fill into vials,

seal and autoclave.

l-Cyclohexyl-2,3-dioxo-5-( 2 dimethylaminoethyl)-4- What IS claimed is:

phenylpiperazine Hydrochloride. A Solution of gfams mole) of 7 1.Acompound selected from 5-(2-am1noethyl)-2,3- dioxopiperazmes having theformula:

2,3-dioxol -cyclohexyl-4-phenylpiperazine and 5 .5 g.

(0.12 mole)'of dimethylamine in 200 ml. of ethanol was heated 'at'130140C. for 24 hours. The mixture Y t V was concentrated in vacuoa'ndthe residue partitioned 1 1| between chloroform and dilute sodiumhydroxide soluo N CHCHa Am tion. The chloroform layer was dried withsodium sulfr "fate, concentrated and the residue crystallized from 0water-methanol. The product weighed 5 g. and melted i I at l88l92C. Thebase was mixed'with l50r'nl. of 1 ethanol, the mixture heated tothereflux point and hy- 40 R drogen chloride passed into the hotsolution until the solution remained acidic. Methyl isobutyl ketone 7ml.) was added to the hot solution which was allowed wh l i tocool'slowly. The hydrochloride s lt which was ob- R is selected from thegroup consisting of lower-alkyl tainedwei ghed 6.5 g. (28%)and melted at315C. 4-5 and Y Y 1 Analysis: Calculated for C, H, N5CIO,: C, 63.22; H,7.96; N, ll.06 Found: 5 C, 63;. 33; H, 7.95; N, l0.96

Formulation and Administration R is phenyl,

Am is selected from the group consisting of methylamino, isopropylaminoand dimethylamino and pharmaceutically acceptable acid addition saltsthereof.

Effective quantities of any, of the foregoingpharmaicolo'gically activecompounds may be administered to aliving animal bodyin any one ofvarious ways, for example, orally as in capsules or tablets, andparenterally 'in the form of sterile solutions. The free basic amino 2.A compound of claim 1 which is 2,3-dioxo-5-(2- compounds, whileeffective, are preferably formulateddimethylaminoethyD-l-isopr0pyl-4-phenylpiperazine. and administered inthe form of their non-toxic acid addition salts. A I l The formulationsof Example 9 are representative for the pharmacologically activecompounds of the invention, but have been especially designed to embody,as 4. A compound f claim 1 i h i 5 2-ai active ingredient'the free basiccompounds of Exam- I th I th I G, h l t ples l, 2, 7 or 8 or theirhydrochlorides. y ammoe y [OX0 e y p eny plperazme 3. A compound ofclaim 1. which is 5-(2-dime- .thylaminoethyD- t 2,3.dioxol-methyl-4-phenylpipe razine.

- y 5 5. A compound of claim 1 which is l-cyclohexyl-2,3- EXAMPLE 9dioxo-5-(Z-dimethylaminoethyl)-4-phenylpip erazine. Formulations 1.Capsules Capsules of 250 mg. of active ingredient are prepared.

1. A COMPOUND SELECTED FROM 5-(2-AMINOETHYI)-2,3-DIOXOPIPERAZINES HAVINGTHE FORMULA:
 2. A compound of claim 1 which is2,3-dioxo-5-(2-dimethylaminoethyl)-1-isopropyl-4-phenylpiperazine.
 3. Acompound of claim 1 which is 5-(2-dimethylaminoethyl)-2,3-dioxo-1-methyl-4-phenylpiperazine.
 4. A compound of claim 1 which is5-(2-dimethylaminoethyl)-2,3-dioxo-1-ethyl-4-phenylpiperazine.
 5. Acompound of claim 1 which is1-cyclohexyl-2,3-dioxo-5-(2-dimethylaminoethyl)-4-phenylpiperazine.